Leiomyomas of the uterine body: Molecular-genetical aspects of formation and development

Authors: D. Dvorská;  J. Višňovský;  D. Braný;  J. Danko
Authors‘ workplace: Gynekologicko-pôrodnícka klinika JLF UK a UNM, Martin, Slovenská republika, prednosta prof. MUDr. J. Danko, CSc.
Published in: Ceska Gynekol 2016; 81(1): 48-52


An overview of the molecular-genetical aspects of formation and development of leiomyomas of the uterine body.

A review article.

Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic.

An analysis of the literature using database search engines PubMed, Blast, Science direct and Web of Knowledge focused on tumorigenesis of leiomyoma.

Benign uterine leiomyomas, also known as myoma, fibroids or fibromyomas are the most common tumours located in the pelvic area of women. The prevalence of this disease reaches, on the global scale, values higher than 50%, depending on the ethnicity even up to 80% of women of reproductive age. Despite such a high value, the origin of leiomyomas is still unknown. The main reason is the heterogeneity of the disease, and a number of factors that influence their development. In the case of leiomyomata occurrence, it has so far been observed several genome rearrangements and a number of aberrantly expressed genes. There are several reasons for overexpression or underexpression of a particular gene, from a point mutation in the exon region of the gene, promoter or other regulatory sequences to epigenetic modifications, most commonly the nature of methylation, or more precisely inadequate regulation short molecule miRNA. Many of these genes belong to the group of tumour-suppressor genes, or more precisely to genes, which can affect the cell cycle in a different way and thus can affect even the cell division. The aim of this work is to describe the various factors influencing the formation of leiomyomas and their impact on tumorigenesis.

leiomom, fibroid, mesenchymal tumour, methylation, epigenetics


1. Ahmad, ST., Arjumand, W., Seth, A., et al. Methylation of the APAF-1 and DAPK-1 promoter region correlates with progression of renal cell carcinoma in North Indian population. Tumor Biol, 2012, 33, 2, p. 395–402.

2. Arslan, A., Gold, LI., Mittal, K., et al. Gene expression studies provide clues to the pathogenesis of uterine leiomyoma, new evidence and a systematic review. Hum Reprod, 2005, 20, 4, p. 852–863.

3. Asada, H., Yamagata, Y., Taketani, T., et al. Potential link between estrogen receptor-alpha gene hypomethylation and uterine fibroid formation. Mol Hum Reprod, 2008, 14, 9, p. 539–545.

4. Bachmann, IM., Halvorsen, OJ., Collett, K., et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol, 2006, 24, 2, p. 268–273.

5. Baird, DD., Dunson, DB., Hill, MC., et al. High cumulative incidence of uterine leiomyoma in black and white women, ultrasound evidence. Amer J Obstet Gynec, 2003, 188, 1, p. 100–107.

6. Bednář, B. Základy klasifikace nádorů a jejich léčení. Praha: Avicenum 1987, s. 737.

7. Burns, KA., Kenneth, S., Korach, A., et al. Estrogen receptors and human disease, an update. Arch Toxicol, 2012, 86, 10, p. 1491–1504.

8. Cook, JD., Walker, CL. The Eker rat: establishing a genetic paradigm linking renal cell carcinoma and uterine leiomyoma. Curr Mol Med, 2004, 4, 8, p. 813–824.

9. Eisenberg-Lerner, A., Kimchi, A. DAPk silencing by DNA methylation conveys resistance to anti EGFR drugs in lung cancer cells. Cell Cycle, 2012, 11, 11, p. 2051.

10. Fitzgerald, JB., Chennathukuzhi, V., Koohestani, F., et al. Role of microRNA-21 and programmed cell death 4 in the pathogenesis of human uterine leiomyomas. Fertil Steril, 2012, 98, 3, p. 726–734. e2.

11. Flake, GP., Andersen, J., Dixon, D. Etiology and pathogenesis of uterine leiomyomas, a review. Environ Health Perspect, 2003, 111, 8, p. 1037–1054.

12. Georgieva, B., Milev, I., Minkov, I., et al. Characterization of the uterine leiomyoma microRNAome by deep sequencing. Genomics, 2012, 99, 5, p. 275–281.

13. Greathouse, KL., Cook, JD., Lin, K., et al. Identification of uterine leiomyoma genes developmentally reprogrammed by neonatal exposure to diethylstilbestrol. Reprod Sci, 2008, 15, 8, p. 765–778.

14. Christoph, F., Kempkensteffen, C., Weikert, S., et al. Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer. Br J Cancer, 2006, 95, 12, p. 1701–1707.

15. Christoph, F., Hinz, S., Kempkensteffen, C., et al. mRNA expression profiles of methylated APAF-1 and DAPK-1 tumor suppressor genes uncover clear cell renal cellcarcinomas with aggressive phenotype. J Urol, 2007, 178, 6, p. 2655–2659.

16. Chuang, TD., Luo, X., Panda, H., et al. miR-93/106b and their host gene, MCM7, are differentially expressed in leiomyomas and functionally target F3 and IL-8. Mol Endocrinol, 2012, 26, 6, p. 1028–1042.

17. Chuang, TD., Panda, H., Luo, X., et al. miR-200c is aberrantly expressed in leiomyomas in an ethnic-dependent manner and targets ZEBs, VEGFA, TIMP2, and FBLN5. Endocr Relat Cancer, 2012, 19, 4, p. 541–556.

18. Chuang, TD., Khorram, O. miR-200c regulates IL8 expression by targeting IKBKB, a potential mediator of inflammation in leiomyoma pathogenesis. PloS One, 2014, 9, 4, e95370.

19. Ingraham, SE., Lynch, RA., Kathiresan, S., et al. hREC2, a RAD51-like gene, is disrupted by t (12; 14)(q15; q24. 1) in a uterine leiomyoma. Cancer genetics and cytogenetics, 1999, 115, 1, p. 56–61.

20. Kato, K., Iida, S., Uetake, H., et al. Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer. Int J Cancer, 2008, 122, 3, p. 603–608

21. Koike, E., Yasuda, Y., Shiota, M., et al. Exposure to ethinyl estradiol prenatally and/or after sexual maturity induces endometriotic and precancerous lesions in uteri and ovaries of mice. Congenital Anomalies, 2013, 53, 1, p. 9–17.

22. Maekawa, R., Sato, S., Yamagata, Y., et al. Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas. PloS One, 2013, 8, 6, e66632.

23. Mann, ML., Ezzati, M., Tarnawa, ED., Carr, BR. Fumarate hydratase mutation in a young woman with uterine leiomyomas and a family history of renal cell cancer. Obstet Gynec, 2015, 126,1, p. 90–92.

24. Marshall, LM., Spiegelmann, D., Goldman, MB., et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril, 1998, 70, 3, p. 432–449.

25. Mehine, M. Kaasinen, E. Mäkinen, N., et al. Characterization of uterine leiomyomas by whole-genome sequencing. New Engl J Med, 2013, 369, 1, s. 43–53.

26. Moravek, MB., Yin, P., Ono, M., et al. Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications. Hum Reprod Update, 2015, 21, 1, p. 1–12.

27. Navarro, A., Yin, P., Monsivais, D., et al. Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PloS One, 2012, 7, 3, e. 33284.

28. Ohara, N., Morikawa, A., Chen, W., et al. Comparative effects of SPRM asoprisnil J867 on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells. Reprod Sci, 2007, 14, 8, p. 20–27.

29. Ozisik, YY., Meloni, AM., Altungoz, O., et al. Translocation (6; 10)(p21; q22) in uterine leiomyomas. Cancer Genet Cytogenet, 1995, 79, 2, p. 136–138.

30. Qiang, W., Liu, Z., Serna, VA., et al. Down-regulation of miR-29b is essential for pathogenesis of uterine leiomyoma. Endocrinology, 2014, 155, 3, p. 663–669

31. Sato, S., Maekawa, R., Yamagata, Y., et al. Potential mechanisms of aberrant DNA hypomethylation on the x chromosome in uterine leiomyomas. J Reprod Dev, 2014, 60, 1, p. 47–54.

32. Skubitz, KM., Skubitz, AM. Differential gene expression in uterine leiomyoma. J Laborator Clin Med, 141, 5, 2003, p. 297–308.

33. Wang, T., Zhang, X., Obijuru, L., et al. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chromosomes Cancer, 2007, 46, 4, p. 336–347.

34. Wong, L., Brun, JL. Myomectomy, technique and current indications. Minerva Ginecol, 2014, 66, 1, p. 35–47.

35. Yang, Q., Mas, A., Diamond, MP., et al. The mechanism and function of epigenetics in uterine leiomyoma development. Reprod Sci, 2015.

36. Yoo, KH., Hennighausen, L. EZH2 methyltransferase and H3K27 methylation in breast cancer. Intern J Biol Sci, 2012, 8, 1, p. 59–65.

Paediatric gynaecology Gynaecology and obstetrics Reproduction medicine

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